The invention relates to chromanone and thiochromanone derivatives. It concerns the compounds of formula I 
wherein
R1 and R2 independently are hydrogen, acyl, alkoxycarbonyl or alkyl;
either the sulfamoyloxy side chain is bound to the 6 position;
R3 is alkyl; alkenyl; alkinyl; a cycloalkyl moiety optionally substituted by alkyl, alkoxy or halogen; arylalkenyl; arylalkinyl; acyl; cycloalkylalkyl; 3-oxo-2-oxacamphanyl; or is 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl; and
R4 is hydrogen; alkyl; hydroxy; or alkoxy;
or the sulfamoyloxy side chain is bound to the 7 position;
R3 has the significance indicated above for R4; and
R4 has the significance indicated above for R3;
X is O or S; and the symbol - - - is a single or a double bond;
in free form or salt form; hereinafter briefly named xe2x80x9cthe compounds of the inventionxe2x80x9d.
A compound of formula I may be present in free, i.e. neutral or base, form or, where such forms exist, in salt, particularly acid addition salt form. A compound of formula I in free form may be converted into a salt form in conventional manner and vice-versa.
The sulfamoyloxy side chain is bound preferably to the 6 position.
Acyl preferably is the residue of a carboxylic acid, in particular of an alkyl, arylalkyl or aryl carboxylic acid. It preferably is alkylcarbonyl of altogether 2 to 5 carbon atoms, it especially is acetyl. Alkoxycarbonyl preferably is of altogether 2 to 5 carbon atoms, it especially is methoxycarbonyl. Alkyl as a moiety R1 or R2 or as part of a substituent preferably is of 1 to 5 carbon atoms, it especially is methyl. Alkyl as a moiety R3 or R4 preferably is of 1 to 12 carbon atoms, it especially is methyl, ethyl or t-butyl, particularly t-butyl. Alkenyl preferably is of 2 to 5 carbon atoms, it conveniently is ethenyl. Alkinyl preferably is of 2 to 5 carbon atoms, it conveniently is ethinyl.
A cycloalkyl moiety may be monocyclic or polycyclic. When it is monocyclic, it preferably is of 3 to 12 carbon atoms, it especially is cyclopropyl, cyclopentyl or cyclohexyl; when it is polycyclic, it preferably is adamantyl, especially 1-adamantyl; nor-adamantyl; or bicyclo[2.2.2]oct-1-yl. When cycloalkyl is substituted, it preferably is substituted by alkyl.
Arylalkenyl preferably is of 2 to 4 carbon atoms in the alkenylene part thereof. It preferably is 2-phenylethenyl, preferably in the trans configuration. Arylalkinyl preferably is of 2 to 4 carbon atoms in the alkinylene part thereof.
Cycloalkylalkyl preferably is of 1 to 4, especially 1 carbon atom in the alkylene part thereof. The cycloalkyl part thereof may be monocyclic or polycyclic; when it is monocyclic, it preferably is of 3 to 12 carbon atoms, it especially is cyclopentyl or cyclohexyl; when it is polycyclic, it preferably is bicyclo[2.2.1]hept-2-yl.
Alkoxy preferably is of 1 to 4 carbon atoms, it especially is methoxy. Halogen is fluorine, chlorine or bromine, preferably chlorine.
R1 and R2 preferably are hydrogen or alkyl, especially hydrogen. They preferably are identical. R3 preferably is alkyl or cycloalkyl. R4 preferably is hydrogen. X conveniently is O. The symbol - - - preferably is a double bond.
In a preferred subgroup of compounds of the invention R1 and R2 are identical and are hydrogen or methyl, and R3 is t-butyl; cyclopentyl; cyclohexyl; adamantyl; bicyclo[2.2.1]hept-2-ylmethyl; nor-adamantyl; 4-pentylbicyclo[2.2.2]oct-1-yl; 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl; camphanyl; styryl; 2,2,3,3-tetramethylcyclopropyl; or alkyl of 1 to 4 carbon atoms.
In a further preferred subgroup R1, R2 and R4 are hydrogen; the sulfamoyloxy side chain is bound to the 6 position; R3 is a bulky moiety selected from the significances indicated above for R3, preferably branched alkyl of 4 to 12 carbon atoms, such as tert-butyl; a monocyclic cycloalkyl moiety of 5 to 12 carbon atoms or a bi- or tricyclic cycloalkyl moiety of 6 to 10 carbon atoms, each optionally mono- or independently di- or independently trisubstituted by alkyl of 1 to 5 carbon atoms; 3-oxo-2-oxacamphanyl; or 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl; and X and the symbol - - - are as defined above.
A further preferred subgroup of compounds of the invention is the compounds of formula Ip 
wherein
R1p and R2p independently are hydrogen or alkyl;
either the sulfamoyloxy side chain is bound to the 6 position,
R3p with the exception of 3-oxo-2-oxacamphanyl has the significance indicated above for R3, and
R4p is hydrogen;
or the sulfamoyloxy side chain is bound to the 7 position,
R3p is hydrogen, and
R4p with the exception of 3-oxo-2-oxacamphanyl has the significance indicated above for R3; and
X and the the symbol - - - are as defined above;
in free form or salt form.
A further preferred subgroup of compounds of the invention is the compounds of formula Is 
wherein
R1s is hydrogen, methyl, acetyl or methoxycarbonyl;
R2s is hydrogen or methyl;
either the sulfamoyloxy side chain is bound to the 6 position,
R3s is alkyl of 1 to 12 carbon atoms; a monocyclic cycloalkyl moiety of 3 to 12 carbon atoms optionally substituted by methyl; 1-adamantyl; nor-adamantyl; 4-pentylbicyclo[2.2.2]oct-1-yl; 2-phenylethenyl; bicyclo[2.2.1]hept-2-ylmethyl; 3-oxo-2-oxacamphanyl; or 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl, and
R4s is hydrogen;
or the sulfamoyloxy side chain is bound to the 7 position,
R3s is hydrogen, and
R4s is cycloalkyl of 5 to 7 carbon atoms; and
X and the symbol - - - are as defined above;
in free form or salt form.
The invention also provides a process for the preparation of the compounds of the invention comprising
a) sulfamoylating the compounds of formula II 
wherein R3, R4, X and the symbol - - - are as defined above; or
b) for the preparation of the compounds of formula Ia 
xe2x80x83wherein
X, R1, R2 and the symbol - - - are as defined above and
R3xe2x80x2 and R4xe2x80x2 with the exception of alkenyl, alkinyl, arylalkenyl, arylalkinyl and 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl have the significance indicated above for, respectively, R3 and R4,
xe2x80x83reducing the corresponding compounds of formula Ib 
xe2x80x83wherein the substituents are as defined above; or
c) for the preparation of the compounds of formula I wherein at least one of R1 and R2 is alkyl, acyl or alkoxycarbonyl,
N-substituting the compounds of formula I wherein at least one of the substituents R1 and R2 is hydrogen;
and recovering the resultant compounds of formula I in free form or salt form.
The process of the invention is carried out in conventional manner.
Process variant a) is performed using standard conditions for sulfamoylation, e.g. by reacting a compound of formula II with:
xcex1) sulfuryl chloride and sodium- or potassium azide to generate corresponding intermediates wherein the hydrogen atom of tho hydroxy group is replaced with a group xe2x80x94SO2N3, which after reduction of the azide group give compounds of formula I wherein R1 and R2 are hydrogen, or
xcex2) CISO2xe2x80x94NCO, followed by aqueous hydrolysis of the resultant intermediates to yield compounds of formula I wherein R1 and R2 are hydrogen, or
xcex3) a compound of formula III 
wherein R1 and R2 are as defined above and Y is a leaving group, e.g. halogen, preferably chlorine, in an inert solvent, e.g. dimethylformamide, where convenient with addition of an organic base, such as an organic tertiary amine, or an inorganic base, e.g. an alkali(hydrogen)carbonate or alkali hydride, preferably sodium hydride.
Process variant b) may be performed following standard procedures for hydrogenation of double bonds, e.g. catalytically, preferably using hydrogen in combination with a hydrogenation catalyst such as Pd, Pt or Rh, most preferably Pd on charcoal. Starting from compounds of formula I wherein R3 is alkenyl alkinyl, arylalkenyl or arylalkynyl, in a first step of the reaction these groups are reduced. The reaction may be stopped at this stage and the double bond in the chromenone ring remain unchanged. Further reduction gives compounds of formula Ia wherein the symbol - - - is a single bond.
Process variant c) is performed according to standard procedures for N-substitution by alkylation or acylation, conveniently using alkylhalogenides, -sulfates or -mesylates, preferably alkyl iodides, or acyl- or alkoxycarbonylhalides, preferably chlorides, preferably in the presence of a suitable base, such as an alkali carbonate or alkali hydride, conveniently in an inert and preferably polar solvent such as acetone or dimethylformamide, preferably at temperatures of between about xe2x88x9220xc2x0 and about 120xc2x0 C., preferably between room temperature and about 60xc2x0 C.
The resultant compounds of the invention may be recovered from the reaction mixture and isolated and purified in conventional manner. Isomers, such as enantiomers, may be obtained in conventional manner, e.g. by fractional crystallization or asymmetric synthesis from corresponding asymmetrically substituted, e.g. optically active starting materials.
The starting materials and intermediate compounds are either known or can be prepared according to known methods or analogously as described in the Examples.
Structurally related compounds with a sulfamate group are known from WO 97/32872, cited during the International Phase of the present application, the scope of which has been amended in view thereof.